LRIG1 engages ligand VISTA and impairs tumor-specific CD8 <sup>+</sup> T cell responses
Hieu Minh Ta, Dia Roy, Keman Zhang, Tyler Alban, Ivan Jurić, Juan Dong, Prerana Bangalore Parthasarathy, Sachin Patnaik, Elizabeth Delaney, Cassandra Gilmour, Amin Zakeri, Nidhi Shukla, Amit Rupani, Yee Peng Phoon, Caini Liu, Stefanie Avril, Brian Gastman, Timothy A. Chan, Li Lily Wang
Abstract
Immune checkpoint blockade is a promising approach to activate antitumor immunity and improve the survival of patients with cancer. V-domain immunoglobulin suppressor of T cell activation (VISTA) is an immune checkpoint target; however, the downstream signaling mechanisms are elusive. Here, we identify leucine-rich repeats and immunoglobulin-like domains 1 (LRIG1) as a VISTA binding partner, which acts as an inhibitory receptor by engaging VISTA and suppressing T cell receptor signaling pathways. Mice with T cell–specific LRIG1 deletion developed superior antitumor responses because of expansion of tumor-specific cytotoxic T lymphocytes (CTLs) with increased effector function and survival. Sustained tumor control was associated with a reduction of quiescent CTLs (TCF1 + CD62L hi PD-1 low ) and a reciprocal increase in progenitor and memory-like CTLs (TCF1 + PD-1 + ). In patients with melanoma, elevated LRIG1 expression on tumor-infiltrating CD8 + CTLs correlated with resistance to immunotherapies. These results delineate the role of LRIG1 as an inhibitory immune checkpoint receptor and propose a rationale for targeting the VISTA/LRIG1 axis for cancer immunotherapy.